1. ¹Institut de Cardiologie de Montréal, Montréal, Québec, Canada
2. ²Département de médecine, Université de Montréal, Montréal, Québec, Canada
3. ³The Broad Institute of MIT and Harvard, Cambridge, MA, USA
4. ⁴Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
5. ⁵Mount Sinai Hospital IBD Center, University of Toronto, Toronto, Ontario, Canada
6. ⁶Gastrointestinal & Endoscopy Units, IRCCS Hospital, San Giovanni Rotondo, Italy
7. ⁷Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
8. ⁸Inflammatory Bowel Disease Genetics Program, University of Pittsburgh School of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh, PA, USA
9. ⁹Medical Genetics Institute and IBD Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
10. ¹⁰IBD Center, Division of Gastroenterology, Department of Medicine, Yale University, New Haven, CT, USA

Correspondence: Dr JD Rioux, Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Rm S-6200, Montreal, Quebec, Canada H1T 1C8. E-mail: John.David.Rioux@umontreal.ca

Received 25 April 2008; Revised 19 June 2008; Accepted 19 June 2008; Published online 24 July 2008.

Abstract

Inflammatory bowel disease (IBD) is a chronic disorder caused by multiple factors in a genetically susceptible host. Significant advances in the study of genetic susceptibility have highlighted the importance of the innate immune system in this disease. We previously completed a genome-wide linkage study and found a significant locus (IBD6) on chromosome 19p. We were interested in identifying the causal variant in IBD6. We performed a two-stage association mapping study. In stage 1, 1530 single-nucleotide polymorphisms (SNPs) were selected from the HapMap database and genotyped in 761 patients with IBD. Among the SNPs that passed the threshold for replication, 26 were successfully genotyped in 754 additional patients (stage 2). One intronic variant, rs273506, located in the microtubule-associated serine/threonine-protein kinase gene-3 (MAST3), was found to be associated in both stages (pooled P=1.8 10^-4). We identified four MAST3 coding variants, including a non-synonymous SNP rs8108738, correlated to rs273506 and associated with IBD. To test whether MAST3 was expressed in cells of interest, we performed expression assays, which showed abundant expression of MAST3 in antigen-presenting cells and in lymphocytes. The knockdown of MAST3 specifically decreased Toll-like receptor-4-dependent NF-B activity. Our findings are additional proofs of the pivotal role played by modulators of NF-B activity in IBD pathogenesis.